Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.[CH2:16]([S:23][C:24]1[CH:25]=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[N:29][C:28]=2Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.O>[CH2:16]([S:23][C:24]1[CH:25]=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[N:29][C:28]=2[C:4]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=1[O:2][CH3:1])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: Clc1nccc2cc(SCc3ccccc3)cnc12
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(SCc3ccccc3)cnc12
Temperature: 60 °C
Yield: 91.1 %

Procedure:
To a vial charged with 2-methoxy-4-(trifluoromethyl)phenyl boronic acid (Combi-Blocks, San Diego, Calif.) (0.268 g, 1.216 mmol), 3-(benzylthio)-8-chloro-1,7-naphthyridine (0.218 g, 0.760 mmol), and potassium phosphate tribasic (0.189 ml, 2.280 mmol) was added dioxane (3.05 ml) and water (1.016 ml). The mixture was purged with argon prior to the addition of 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (0.054 g, 0.076 mmol). The vessel was sealed and heated to 60° C. overnight. After cooling to ambient temperature, the mixture was loaded directly onto a silica gel loading column and purified with a 40 g HP spherical column (silicycle) (SiliCycle, Inc. Quebec City, Canada) ramping EtOAc in heptane (0 to 35%, then isocratic at 35%) to provide 3-(benzylthio)-8-(2-methoxy-4-(trifluoromethyl)phenyl)-1,7-naphthyridine (0.295 g, 0.692 mmol, 91% yield) as an off-white foam. m/z (ESI) 427.3 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>O>[C:13]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:12])([CH3:10])[CH3:11])[CH2:5][CH2:4]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)C1CCC(CO)CC1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC1CCC(C(C)(C)O)CC1
Reaction time: 0.75 h
Yield: 86 %

Procedure:
A mixture of 258 g (1.5M) of 7,8-dihydroxy-p-menthane, 2700 ml of acetic anhydride and 810 ml of pyridine was kept under stirring for 45 minutes, then it was poured onto ice (1 kg) and water (1000 ml). After its extraction with three fractions of 700 ml each of ether, the combined organic phases were washed with a 10% aqueous solution of NaOH (3×500 ml), water (2×500 ml) and a saturated aqueous solution of NaCl (500 ml). The solvent was evaporated and the residue (284 g) was distilled to give a colorless oil (276 g) having b.p. 108°-110°/0.133 Pa (yield 86%).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].C1CCC(N=C=NC2CCCCC2)CC1.[NH:29](C(OC(C)(C)C)=O)[C@H:30]([C:38]([OH:40])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C=O)C>C(Cl)Cl>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:29][C@H:30]([C:38]([OH:40])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
On the other hand, 2 mmole of Boc-Ala, the 36th amino acid in the amino acid sequence, was dissolved in 5 ml ml of DCM. In an amino acid activating vessel, 2 ml of DCC (0.5M DCM solution) was added to the resulting solution They were reacted for 5 minutes. Thereafter, the reaction product was treated in the same manner as in the Boc-Phe After addition of DMF and subsequent concentration under a nitrogen gas stream, the resulting concentrate was transferred to a reaction vessel so as to conduct a reaction for 20 minutes. The reaction mixture was then washed with 8 ml of DCM (6 times, each, for 20 seconds) and filtered to obtain Boc-Ala-Phe-resin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](O)[N:9]=2)[CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)[CH:13]=[CH:12][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nccc(-c2cc(Cl)ccn2)n1
Product: Clc1ccnc(-c2ccnc(Cl)n2)c1
Reaction time: 3 h

Procedure:
A mixture of 10 g I.28 (4-(4-chloro-pyridin-2-yl)-pyrimidin-2-ol) in 100 ml phosphorus oxychloride was stirred for 3 h at reflux. The solvent was evaporated and the crude 8.1 was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:9][NH2:10])=[C:4]([CH3:20])[CH:3]=1.[C:21]([C:23]1[CH:24]=[C:25]([C:33](O)=[O:34])[C:26]2[CH2:27][CH2:28][CH2:29][CH2:30][C:31]=2[CH:32]=1)#[N:22].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:21]([C:23]1[CH:24]=[C:25]([C:33]([NH:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:20])[CH2:11][CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[O:34])[C:26]2[CH2:27][CH2:28][CH2:29][CH2:30][C:31]=2[CH:32]=1)#[N:22]
Reactant: N#Cc1cc2c(c(C(=O)O)c1)CCCC2
Reactant: Cc1cc(F)ccc1C(CN)CCOC1CCCCO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1cc(F)ccc1C(CCOC1CCCCO1)CNC(=O)c1cc(C#N)cc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
[2-(4-Fluoro-2-methylphenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butyl]amine (0.40 g, 1.4 mmol), 3-cyano-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (see WO 00/34243; 0.32 g, 1.6 mmol) and DCC (0.35 g, 1.7 mmol) were mixed with CH2Cl2 (5 mL). The mixture was stirred at room temperature overnight and then filtrated and the solvent was evaporated. The product was purified by chromatography on silica gel using methanol and CH2Cl2 (0%-2% methanol). There was obtained 600 mg (91%) of 3-cyano-N-[2-(4-fluoro-2-methylphenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butyl]-5,6,7,8-tetrahydronaphthalene-1-carboxamide as a foam. 1H NMR (500 MHz, CDCl3): 1.0-1.9 (m, 9H), 2.0-2.1 (m, 1H), 2.4 (d, 3H), 2.6-2.8 (m, 4H), 3.2-3.8 (m, 7H), 4.4-4.5 (d, 1H), 6.0-6.2 (m, 1H), 6.9 (m, 2H), 7.1-7.3 (m, 2H), 7.4 (s, 1H). LCMS: m/z 463 (M−1)−.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C1CCC(N=C=NC2CCCCC2)CC1.CS([O:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:45])[NH2:44])[CH:39]=2)[CH:34]=1)(=O)=[O:30]>N1C=CC=CC=1>[C:6](=[O:7])([OH:30])[OH:8].[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43](=[NH:45])[NH2:44])[CH:39]=2)[CH:34]=1)=[O:7]
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)c1
Product: O=C(O)O
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
To 70 ml of dried pyridine, were added 2.9 g of 3-dimethylaminobenzoic acid and 4.4 g of DCC. The mixture was stirred for 30 minutes while cooling in ice. After addition of 5.0 g of 6-amidino-2-naphthol methanesulfonate, the mixture was further stirred for one hour under cooling in ice and then overnight at room temperature. The reaction mixture was filtered and the filtrate was mixed with ethyl ether. The precipitate which was formed was collected by filtration, dissolved in a small quantity of methanol, and added to a saturated aqueous sodium hydrogencarbonate solution while being stirred. The precipitated crystals were collected by filtration to obtain 3.8 g of 6-amidino-2-naphthyl 3-dimethylaminobenzoate carbonate having a melting point of above 120° C. (decomp.). The crystals were suspended in ethanol, mixed with 1.4 g of acetic acid and stirred to form a clear solution from which crystals were precipitated after some time. The crystals were collected by filtration and recrystallized from ethanol to obtain 2.5 g of a white powder of 6-amidino-2-naphthyl 3-dimethylaminobenzoate acetate.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+].Cl>C(O)C.O>[C:17]([O:16][C:14]([NH:13][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C@@H:4]([OH:21])[CH2:3][OH:2])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CO
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 72.6 %

Procedure:
A solution of N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenylbutyric acid methyl ester 99 g dissolved in ethanol 130 ml was kept at 15-25° C. and mixed with sodium borohydride 15.7 g and stirred at 15-25° C. for 2.5hrs. The reaction solution was diluted with water, adjusted with 6N-HCl to pH 2.5-3.5 and thereafter the solvent was distilled away to half the volume of the resultant solution, and then ethyl acetate was added to the solution. The solution thus obtained was washed with water and aqueous 10% sodium chloride solution successively to separate an organic phase. The solvent in the organic phase was distilled away and then ethyl acetate was added to the resultant concentrated solution to cool it and n-heptane was added to the solution halfway. Further n-heptane was added to the cloudy solution obtained. Thereafter, the solution was stirred at 10° C. to deposit crystals, which were filtered and dried in vacuum to obtain the N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-butanol(65.4 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][CH2:13][CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1>>[F:1][C:2]1[CH:9]=[C:8]([CH:10]2[C:16]3[NH:17][CH:18]=[N:19][C:15]=3[CH2:14][CH2:13][NH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: NCCc1c[nH]cn1
Reactant: N#Cc1ccc(C=O)cc1F
Product: N#Cc1ccc(C2NCCc3nc[nH]c32)cc1F

Procedure:
2-Fluoro-4-formyl-benzonitrile (as described in Example 29, Step A) (0.268 g, 1.79 mmol) and histamine (0.200 g, 1.79 mmol) were heated neat at 120° C. for 1.5 h. The molten liquid was cooled to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=[C:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][CH3:22].I([O-])(=O)(=O)=[O:24].[Na+].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.CO>[CH3:22][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:3]1[N:2]([CH3:1])[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[N:4]=1)=[O:24]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1c(-c2ccccc2S(C)=O)nc2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a mixture of 3-methyl-2-(2-methylsulfanylphenyl)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.32 g), methanol (4 ml) and water (6 ml), sodium periodate (0.42 g) was added under ice-cooling. The mixture was heated to room temperature, and stirred for 1 hour, and then heated to 40° C., and stirred with heating for further 1 hour. Into the reaction mixture cooled to room temperature saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution were poured, and extracted with chloroform 2 times. The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.32 g of 2-(2-methylsulfinylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13]Cl)[CH2:7][CH2:6][CH2:5]2.[I-:15].[Na+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][I:15])[CH2:7][CH2:6][CH2:5]2
Reactant: ClCCN1CCCc2cc(Br)ccc21
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Brc1ccc2c(c1)CCCN2CCI
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A suspension of 6-bromo-1-(2-chloroethyl)-1,2,3,4-tetrahydroquinoline (compound 2, 1.80 g, 6.56 mmol) and sodium iodide (9.83 g, 65.6 mmol) in acetone (50 mL) was heated to reflux for 2 days at which time TLC analysis showed residual starting material 2. At this time a further portion of sodium iodide (19.66 g, 132.0 mmol) was added and the suspension refluxed for 5 days. The mixture was cooled to room temperature, filtered through a pad of celite and the filtrate concentrated to yield a yellow solid. The solid was taken up in a mixture of ethyl acetate/hexanes (150 mL) and filtered through a pad of silica gel, and the pad rinsed further with EtOAc/Hexanes. The filtrate was concentrated to yield a yellow oil, 3 (2.19 g, 91%). 1H-NMR (CDCl3) δ 7.12 (dd, 1H, J=8.7, 2.5 Hz), 7.09-7.04 (m, 1H), 6.42 (d, 1H, J=8.7), 3.65-3.60 (m, 2H), 3.33 (t, 2H, J=5.6 Hz), 3.25-3.19 (m, 2H), 2.72 (t, 2H, J=6.3 Hz), 1.98-1.90 (m, 2H). MS (ESI+): 366/368 (MH+, 100).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][N:22]=[CH:21]2>C(O)(C)C>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][N:22]=[CH:21]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: NCCNc1cccc2cn[nH]c12
Solvent: CC(C)O
Product: OC(CNCCNc1cccc2cn[nH]c12)COc1ccccc1
Yield: 67 %

Procedure:
3.0 g. Phenyl glycidyl ether and 7.0 g. 7-(2-aminoethylamino)-indazole are stirred for 10 hours at 70° C. in 20 ml. isopropyl alcohol. The reaction mixture is then evaporated and purified chromatographically on a silica gel column in the manner described in Example 24. The residue of the pure fractions is digested with ethyl acetate and then recrystallized from ethyl acetate, with the use of active charcoal and fullers' earth. There are obtained 2.3 g. (35% of theory) of the desired product in the form of colorless crystals; m.p. 117°-119° C.
Reaction SMILES: [C:1]([C:3](=[C:8](SC)[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6]C)=O)#[N:2].Cl.[CH:19]1([CH2:24][C:25]([NH2:27])=[NH:26])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>CN(C=O)C.O>[CH:19]1([CH2:24][C:25]2[NH:27][C:4](=[O:6])[C:3]([C:1]#[N:2])=[C:8]([NH:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:26]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)C(C#N)=C(Nc1cccnc1)SC
Reactant: N=C(N)CC1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(Nc2cccnc2)nc(CC2CCCC2)[nH]c1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.1 g (0.40 mmol) of methyl 2-cyano-3-(methylsulfanyl)-3-(3-pyridinylamino)-2-propenoate and 0.065 g (0.40 mmol) of 2-cyclopentylethanamidine hydrochloride and 0.16 g (1.60 mmol) of triethylamine are dissolved in 0.5 ml of DMF and stirred at 100° C. overnight. After cooling, the mixture is diluted with 10 ml of water and extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated in vacuo, and the residue is purified by flash chromatography (mobile phase: dichloromethane/methanol 200:1, 100:1, 50:1). 78 mg (64% of theory) of the product are obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.C[C:12]([NH2:19])(SC)[CH2:13][N+:14]([O-:16])=[O:15].[CH3:20]CO>>[Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:12]([NH:19][CH3:20])=[CH:13][N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: CSC(C)(N)C[N+](=O)[O-]
Reactant: CCO
Reactant: NCc1ccc(Cl)nc1Cl
Product: CNC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1Cl

Procedure:
A mixture of 1.2 g (0.007 mole) of (2,6-dichloro-3-pyridylmethyl)amine and 1 g (0.007 mole) of 1-methyl- amino-1-methylthio-2-nitroethane was refluxed in 50 ml of EtOH for 6 hours. After cooling, the reaction mixture was concentrated and the resulting crystals were collected by filtration, washed with CH2Cl2 and a small amount of EtOH in that order and dried. The procedure gave 0.53 g of the title compound as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])C=C.[C:20]([O-])(=[O:23])[CH:21]=C>[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:23][CH2:20][CH2:21][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:9])[C:11]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[CH:4][CH:3]=1
Reactant: C=CC(=O)[O-]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Product: CC(C(=O)OC(C)(C)C)c1ccc(CCO)cc1

Procedure:
p-Bromophenylethanol is first condensed with t-butyl acrylate under conditions of the palladium acetate catalyzed Heck reaction. The resulting acrylate is hydrogenated with palladium on charcoal catalyst to yield t-butyl p-(2-hydroxyethyl)-phenylpropionate, which is converted to the corresponding tosylate by treatment with tosyl chloride in pyridine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([OH:18])=O.CN(C)C=O.[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[NH2:33]>ClCCl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[NH:33][C:16](=[O:18])[CH2:15][C:9]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=1[Cl:7]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cccnc1N
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1NC(=O)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
Oxalyl chloride (0.14 ml) was added dropwise to a solution of (2,4-dichloro-phenyl)-acetic acid (270 mg) in dichloromethane (10 ml) at ambient temperature. A drop of N,N-dimethylformamide (“DMF”) was added to initiate the reaction. The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated to give a colourless oil which was dissolved in dichloromethane (3 ml). The mixture was added dropwise to a cooled (−5° C.) slurry of 2-amino-nicotinic acid methyl ester (200 mg) (Example 1.1), 4-dimethylaminopyridine (“DMAP”) (32 mg) and pyridine (0.19 ml) in dichloromethane (5 ml). The reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between dichloromethane and aqueous hydrochloric acid (2M). The phases were separated. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: acetone/iso-hexane ratio 1:9 to 2:8) to give 2-[2-(2,4-dichloro-phenyl)-acetylamino]-nicotinic acid methyl ester as a light yellow gum (197 mg). 1H-NMR (400 MHz, CDCl3): 10.81 (bs, 1H), 8.59-8.60 (m, 1H), 8.29-8.31 (m, 1H), 7.42-7.44 (m, 1H), 7.34-7.36 (m, 1H), 7.23-7.27 (m, 1H), 7.07-7.11 (m, 1H), 4.08 (s, 2H), 3.90 (s, 3H) ppm.
Reaction SMILES: [CH3:1]S(Cl)(=O)=O.O[C:7]1[C:12]([CH3:13])=[C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:10]=[CH:9][N:8]=1.C(=O)([O-])O.[Na+].[SH:26][C:27]1[NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=2[N:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)C.C(N(CC)CC)C>[CH3:20][O:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:1][S:26][C:27]2[NH:31][C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]=2)[C:12]=1[CH3:13]
Reactant: COCCCCOc1ccnc(O)c1C
Reactant: CS(=O)(=O)Cl
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: COCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 31.5 %

Procedure:
611 mg of triethylamine and 686 mg of methanesulfonyl chloride were added to a solution of 0.84 g of crude 2-hydroxy-4-(4-methoxybutoxy)-3-methylpyridine in 30 ml of dichloromethane at -20° C. under stirring and dehumidifying to obtain a mixture. This mixture was gradually brought to a room temperature, followed by the addition of a saturated aqueous solution of sodium hydrogencarbonate. The obtained mixture was stirred for 30 minutes and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under a reduced pressure to remove the chloroform. Thus, a red oil was obtained. 560 mg of 2-mercapto-1H-benzimidazole and 30 ml of ethanol were added to this oil. The obtained mixture was stirred at a room temperature for 30 minutes, made basic with a 2N aqueous solution of sodium carbonate and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under a reduced pressure to remove the chloroform. The obtained residue was chromatographed over a silica gel column and eluted with ethyl acetate/n-hexane to obtain 0.42 g of an oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[N:19]=[C:20]([CH2:23][C:24]([OH:26])=O)[S:21][CH:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:60]1[CH2:65][CH2:64][CH:63]([CH2:66][NH2:67])[CH2:62][CH2:61]1>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:8]([C:18]2[N:19]=[C:20]([CH2:23][C:24]([NH:67][CH2:66][CH:63]3[CH2:64][CH2:65][O:60][CH2:61][CH2:62]3)=[O:26])[S:21][CH:22]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(-c2c(-c3csc(CC(=O)O)n3)cnn2C(C)(C)C)cc1
Reactant: NCC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(-c2c(-c3csc(CC(=O)NCC4CCOCC4)n3)cnn2C(C)(C)C)cc1
Yield: 17.3 %

Procedure:
A solution of the compound (54 mg, 0.15 mmol) obtained in step 7, HATU (66.3 mg, 0.17 mmol), DIEA (0.030 mL, 0.17 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.020 mL, 0.17 mmol) in DMF (2 mL) was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 80→100% ethyl acetate/hexane) to give the title compound (12 mg, 0.026 mmol, 18%)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:7]1([C:13]2[CH:21]=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>C(Cl)Cl>[CH2:5]([O:4][C:2]([N:22]1[CH:27]=[CH:26][CH:25]([C:21]2[C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:24]=[N:23]1)=[O:3])[CH3:6]
Reactant: c1ccnnc1
Reactant: c1ccc(-c2cc3ccccn3n2)cc1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)N1C=CC(c2c(-c3ccccc3)nn3ccccc23)C=N1
Temperature: 10 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
Ethyl chloroformate (3.38 g) was added dropwise with stirring to a solution of 2-phenylpyrazolo[1,5-a]pyridine (2.54 g) and pYridazine (5.00 g) in methylene chloride (5.0 ml) at 10° C. After being stirred at 10° C. for 1 hour and then at room temperature for 2 hours, the reaction mixture was poured onto ice-water (100 ml) and extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride aqueous solution (100 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (150 g) with a mixture of chloroform and n-hexane (1:1) as an eluant. The fractions containing main-product [compound (A)] were combined and evaporated in vacuo to give 3-(1-ethoxycarbonyl-1,4-dihydropyridazin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.42 g).